Project Summary Systemic elevation in chronic, low grade inflammation is seen across almost all peripheral organ systems with aging. This systemic ?inflammaging? has a major impact on brain function and leaves the brain vulnerable to injury. The main goal of this proposal is to investigate and manipulate the mechanisms by which chronic inflammation impacts the response to ischemic stroke, the leading cause of long-term disability in the elderly. Experimental, clinical, and epidemiological studies demonstrate that peripheral immune challenges lead to detrimental effects in the central nervous system (CNS) such as sickness behavior and delirium. Conversely, although much more recently recognized, a primary CNS insult can also trigger dramatic changes in the periphery. We hypothesize that increased peripheral inflammation contributes to the high mortality and poor functional recovery seen after stroke in aged animals. Reversing peripheral ?inflammaging? by manipulation of peripheral factors will decrease the number of activated T cells found in the aged CNS and reduce microglia activation, leading to enhanced recovery after experimental stroke. This hypothesis is supported by recent studies demonstrating that age-related deficits in neurogenesis and memory can be reversed by administration of systemic factors found in young blood and from our own data that shows rejuvenation of the aged peripheral immune system with young bone marrow reduces mortality and enhances behavioral recovery after stroke. Using animal models, we will examine the relationship between age-related changes in cellular and humoral inflammation and ischemic stroke outcome, which will allow for the identification of novel age-appropriate therapeutic targets. Our preliminary data suggests the pro-inflammatory phenotype seen in aged mice contributes to poor stroke outcome, and that this can be reversed by bone marrow transplantation (BMT) from a young donor. We will first determine whether this rejuvenation phenotype leads to long-lasting functional improvements after stroke. The effects of BMT on the phenotype/function of age-related CNS resident immune cells (CD8+ T cells and microglia) will be then examined in chimeras developed from mice lacking mature lymphocytes. Heterochronic parabiosis results in a similar ?rejuvenation? phenotype in models of age-related cognitive decline. We will combine this technique with proteomic screens and RNA sequencing to identify novel ?pro-rejuvenation? factors (Aim 2a) and investigate how these interact with intrinsic CNS immune cells. Finally plasma exchange will be investigated to determine if these therapeutic benefits can be recapitulated without replacement of cellular elements (Aim 2b).